The effectiveness of influenza vaccine over multiple influenza seasons in children less than 5 years of age has not been well studied. This is especially important to assess because of the recent recommendation for routine influenza vaccination in childhood. We conducted a matched case-control study to assess the vaccine effectiveness of Trivalent Inactivated Influenza Vaccine (TIV) against laboratory-confirmed, medically attended influenza among children 6-59 months of age at the start of each influenza season from 1999-2000 through 2006-2007 in Olmsted County, MN, USA. The children vaccinated against influenza accordingly to the 2007 ACIP guidelines had a lower risk of laboratory-confirmed medically attended influenza illness (Odds Ratio: 0.14, 95% Confidence Interval: 0.03-0.71) than the unvaccinated children. TIV provided strong protection against laboratory-confirmed medically attended influenza in children 6-59 months old in the fully vaccinated group. This trend continued in the partially vaccinated group (Odds Ratio: 0.27, 95% Confidence Interval: 0.07-0.97) but the protection provided maybe suboptimal.